Project Summary Amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD) are two related neurodegenerative diseases which share overlapping clinical, pathologic and genetic features. The ALS-FTD spectrum of diseases is uniformly fatal, and there is neither treatment nor cure. There is a remarkable convergence of pathologic and genetic data which indicate that abnormal RNA metabolism is linked to neurodegeneration in ALS and FTD. The overall goal of this proposal is define the molecular neuropathology of ALS and FTD using human brain tissue. Understanding the molecular aberrations associated with specific brain pathologies will reveal insights into the molecular pathogenesis of ALS/FTD. Novel methods are presented in which pathologic proteins or neurons are isolated from human brain for deep molecular analysis. Two specific aims are proposed which will (1) determine the molecular composition of pathologic TDP-43 protein inclusions, and (2) identify the abnormalities in RNA processing due to the loss of normal nuclear TDP- 43 protein. These studies will further our understanding of TDP-43 proteinopathies by using highly innovative techniques to study human brain tissue with advanced molecular techniques.